Inhibitory Effect on PARP
Poly(adenosine 5′-diphosphate-ribose) polymerase [poly(ADP-ribose) polymerase, PARP], which is also known as poly(ADP-ribose) synthetase (PARS), is a chromatin-bound nuclear enzyme of eukaryotic cells, of which approximately 2×105 molecules are present per nucleus. PARP is, according to the most recent research results, involved in the pathogenesis of various disorders, and thus inhibition of PARP enzyme activity may have beneficial effects on the course of disorders in preclinical animal models (Cristina Cosi, Expert Opin. Ther. Patents, 2002, 12, 1047-1071 and L. Virag and C. Szabo, Pharmacol. Rev., 2002, 54, 1-54). Poly(ADP-ribose) polymerase occurs in all eukaryotic organisms with the exception of yeast, and is part of the genome surveillance network to protect the genetic information from genotoxic influences. DNA damage induces the enzymatic activity of poly(ADP-ribose) polymerase, leading under physiological conditions to repair of the errors recognized by the enzyme in the DNA. However, in pathological situations, poly(ADP-ribose) polymerase may be strongly activated by free-radical oxygen species—as is the case in ischemia, hypoxia, reperfusion or in inflammatory processes—resulting in consumption by the enzyme of large amounts of its substrate NAD. This depletion of NAD is one of the reasons for the death of cells to be observed in the affected tissue (the so-called energy crisis theory). The therapeutic use of PARP inhibitors is in the prevention or reduction of this NAD depletion in tissue. Apart from the role, described herein, in signal transmission ranging from oxidative stress in cells to NAD depletion, further cellular functions of PARP are suggested in the current literature, and these might likewise play a role in the molecular mechanism of action of PARP inhibitors in pathological situations (A. Chiarugi, Trends Pharmacol. Sci., 2002, 23, 122-129). Irrespective of this unresolved discussion about the molecular mechanism of action, the therapeutic efficacy of various PARP inhibitors has been shown in several preclinical animal models: thus, for example, for acute myocardial infarction, acute renal failure, cerebral ischemia (stroke), neurodegenerative disorders (e.g. a model of Parkinson's disease), diabetes, xenobiotic-induced hepatotoxicity, arthritis, shock lung, septic shock and as sensitizer in the chemotherapy of neoplastic disorders (summarized in L. Virag and C. Szabo, Pharmacol. Rev., 2002, 54, 1-54).
It has specifically been possible to show that PARP inhibitors bring about morphological and functional improvements not only in acute myocardial infarction (J. Bowes et al., Eur. J. Pharmacol., 1998, 359, 143-150; L. Liaudet et al., Br. J. Pharmacol., 2001, 133, 1424-1430; N. Wayman et al., Eur. J. Pharmacol., 2001, 430, 93-100), but also significantly better cardiac functions have been measured in chronic heart failure during PARP inhibitor treatment (P. Pacher, J. Am. Coll. Cardiol., 2002, 40, 1006-1016). The hypoperfusion like that which, in the infarcted heart, brings about losses of function of the organ through death of cells also appears in stroke at the start of the chain of events which leads to losses or complete failure of individual regions, and thus functions, of the organ. Accordingly, it has been possible to show the efficacy of PARP inhibitors—besides the genetic ablation of the PARP-1 gene (M. J. L. Eliasson et al., Nat. Med., 1997, 10, 1089-1095)—also in models of cerebral ischemia (K. Takahashi et al., L. Cereb. Blood Flow Metab., 1997, 11, 1137-1142), of MPTP-induced neurotoxicity (C. Cosi et al., Brain Res., 1996, 729, 264-269) and of neuronal excitotoxicity (A. S. Mandir et al., J. Neurosci., 2000, 21, 8005-8011). A further finding which is very important in connection with cardiovascular disorders is the efficacy of PARP inhibition in the ischemically damaged kidney, where improvements in the filtration function of the organ have likewise been found in animals treated with PARP inhibitors compared with those treated with placebo (D. R. Martin et al., Am. J. Physiol. Regulatory Integrative Comp. Physiol., 2000, 279, R1834-R1840). In contrast to the acute ischemic insults of the abovementioned disorders, chronic PARP activation occurs in various pathologies such as, for example, in diabetes. The efficacy of PARP inhibitors has been demonstrated both in preclinical models of type I diabetes (W. L. Suarez-Pinzon et al., Diabetes, 2003, 52, 1683-1688) and in those of type II diabetes (F. G. Soriano et al., Nat. Med., 2001, 7, 108-113; F. G. Soriano et al., Circulation, 2001, 89, 684-691). The beneficial effect of PARP inhibitors in type I diabetes is attributable to their antiinflammatory properties, which it has also been possible to show in further preclinical models, such as of chronic colitis (H. B. Jijon et al., Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 279, G641-G651), of collagen-induced arthritis (H. Kröger et al., Inflammation, 1996, 20, 203-215) and in septic shock (B. Zingarelli et al., Shock, 1996, 5, 258-264). In addition, PARP inhibitors have a sensitizing effect on tumors in chemotherapy on mice (L. Tentori et al., Blood, 2002, 99, 2241-2244).
Background References
It has been disclosed in the literature (for example C. Cosi, Expert Opin. Ther. patents, 2002, 12, 1047-1071; Southan et al., Current Medicinal Chemistry, 2003, 10, 321-340) that many different classes of chemical compounds can be used as PARP inhibitors, such as, for example, derivatives of indoles, benzimidazoles, isoquinolinols or quinazolinones. Many of the previously disclosed PARP inhibitors are derivatives of a bi- or polycyclic basic structure.
The use of isoquinolinone derivatives as PARP inhibitors is described for example in WO 02/090334. The isoquinolinone derivatives described therein are without exception based on a basic structure in which the second ring of the bicycle (with carbon atoms 5, 6, 7 and 8) is in aromatic form, whereas the ring having the amide group of the bicycle may optionally be hydrogenated in position 3 and 4. The isoquinolinone derivatives disclosed in EP-A 0 355 750, which can likewise be used as PARP inhibitors, are based on the same aromatic basic structure.
A large number of PARP inhibitors can be inferred from the general formula (I) disclosed in WO 99/11624. Disclosed therein inter alia is a tetrahydro-2H-isoquinolin-1-one derivative which has an aminoethyl substituent in position 4. A further possibility is for the radical R6 in formula (I) also to be aryl, although it is not mentioned that this aryl radical optionally has further substituents. An aryl radical for R6 is specifically described in WO 99/11624 only for examples in which the ring defined by Y in the basic structure both is unsaturated and has heteroatoms. The specific combination of a 5,6,7,8-tetrahydro-2H-isoquinolin-1-one derivative which is substituted in position 4 either directly or via a linker by an aryl or heteroaryl radical is, however, neither disclosed in nor obvious from WO 99/11624. It is thus evident that the compounds of the invention are not disclosed by WO 99/11624. The present invention does not relate to compounds as such which are explicitly disclosed in WO 99/11624.
J. Rigby et al., J. Org. Chem. 1984, 4569-4571, describe, within the framework of a general synthetic method for the cyclization of vinyl isocyanates, the preparation of 4-phenyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one by cyclocondensation of an enamine and of a vinyl isocyanate. No association is made between the compounds described in J. Rigby et al. and any use as pharmaceuticals. The present invention does not relate to the compounds explicitly disclosed by J. Rigby et al. as such.